The E3 Ubiquitin Ligase, CHIP/STUB1, Inhibits Aggregation of Phosphorylated Proteoforms of Microtubule-associated Protein Tau (MAPT)

• Published in: Journal of molecular biology 2023-06, Vol.435 (11), p.168026-168026, Article 168026
• Main Authors: Nadel, Cory M., Thwin, Aye C., Callahan, Matthew, Lee, Kanghyun, Connelly, Emily, Craik, Charles S., Southworth, Daniel R., Gestwicki, Jason E.
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - metabolism; Humans; intrinsically disordered protein; molecular biology; Molecular Chaperones - chemistry; phospho-degrons; Phosphorylation; Protein Aggregates; protein aggregation; protein–protein interactions; solubility; tau Proteins - chemistry; tauopathy; tetratricopeptide repeats; ubiquitin-protein ligase; Ubiquitin-Protein Ligases - chemistry; Ubiquitination
• ISSN: 0022-2836; 1089-8638
• DOI: 10.1016/j.jmb.2023.168026

[Display omitted] •CHIP binds more tightly to phosphorylated tau (p-tau) than unmodified tau.•CHIP suppresses p-tau aggregation and rapidly ubiquitinates it in vitro.•In a cellular model, CHIP restricts p-tau seeding. Hyper-phosphorylated tau accumulates as insoluble fibrils in Alzheimer’s disease (AD) and related dementias. The strong correlation between phosphorylated tau and disease has led to an interest in understanding how cellular factors discriminate it from normal tau. Here, we screen a panel of chaperones containing tetratricopeptide repeat (TPR) domains to identify those that might selectively interact with phosphorylated tau. We find that the E3 ubiquitin ligase, CHIP/STUB1, binds 10-fold more strongly to phosphorylated tau than unmodified tau. The presence of even sub-stoichiometric concentrations of CHIP strongly suppresses aggregation and seeding of phosphorylated tau. We also find that CHIP promotes rapid ubiquitination of phosphorylated tau, but not unmodified tau, in vitro. Binding to phosphorylated tau requires CHIP’s TPR domain, but the binding mode is partially distinct from the canonical one. In cells, CHIP restricts seeding by phosphorylated tau, suggesting that it could be an important barrier in cell-to-cell spreading. Together, these findings show that CHIP recognizes a phosphorylation-dependent degron on tau, establishing a pathway for regulating the solubility and turnover of this pathological proteoform.